Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

A comparison of TAFRO syndrome between Japanese and non-Japanese cases: a case report and literature review.

TAFRO syndrome was first described as a variant of multicentric Castleman's disease with thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly. We report the case of a 25-year-old Caucasian male with diagnosis of TAFRO syndrome and present a literature review. The objective of the study was to compare TAFRO syndrome between Japanese and non-Japanese patients. Cases were included by searching the term "TAFRO" in the Medline database using PubMed between 2010 and 2016. The Student t test and Mann-Whitney U test were used to compare continuous variables. Fisher's exact test was used for categorical variables. Statistical significance was set at p < 0.05. Forty-four cases were included. Thirty-two patients (73%) were of Japanese origin. Japanese patients were significantly older than non-Japanese ones (52.0 ± 13.6 years versus 36.9 ± 19.8 years, p = 0.0064) but there was no difference in gender. Creatinine level on admission was significantly higher in the non-Japanese group (1.87 ± 0.84 mg/dL versus 1.32 ± 0.57 mg/dL, p = 0.0347). There were no significant differences concerning lymphadenopathy, elevated number of megakaryocytes on bone marrow aspiration, autoimmune abnormalities, and the following parameters on admission: platelet count, hemoglobin, albumin, alkaline phosphatase (ALP). Corticotherapy was always used on induction for Japanese patients while it was only used in 75% of the cases on induction in non-Japanese patients (p = 0.0166). Our study was the first to compare TAFRO syndrome according to ethnicity. Japanese patients were significantly older and had a significantly lower creatinine level on admission than non-Japanese patients.

Use of Biologics to Treat Relapsing and/or Refractory Eosinophilic Granulomatosis With Polyangiitis: Data From a European Collaborative Study.

OBJECTIVE: To describe the efficacy and safety of biologics for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: A retrospective European collaborative study was conducted in patients with EGPA who received treatment with biologics for refractory and/or relapsing disease. RESULTS: Among the 147 patients with EGPA included in the study, 63 received rituximab (RTX), 51 received mepolizumab (MEPO), and 33 received omalizumab (OMA). At the time of inclusion, the median Birmingham Vasculitis Activity Score (BVAS) was 8.5 (interquartile range [IQR] 5-13) in the RTX group, while the median BVAS in the OMA group was 2 (IQR 1-4.5) and the median BVAS in the MEPO group was 2 (IQR 1-5). In patients receiving RTX, the median BVAS declined both at 6 months (median 1, IQR 0-4.5) and at 12 months (median 0, IQR 0-2), and the frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 49%, 24%, 24%, and 3%, respectively. For the treatment of glucocorticoid (GC)-dependent asthma, patients who received MEPO had a much better GC-sparing effect and overall response than did patients who received OMA. The frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 15%, 33%, 48%, and 4%, respectively, in the OMA group and 78%, 10%, 8%, and 4%, respectively, in the MEPO group. Remission rates at 12 months were 76% and 82% among patients receiving MEPO at a doses of 100 mg and 300 mg, respectively. CONCLUSION: These results suggest that RTX could be effective in treating relapses of EGPA vasculitis. MEPO is highly effective with a good safety profile in patients with GC-dependent asthma. Our data suggest that 100 mg MEPO monthly could be an acceptable dosage for first-line therapy in selected instances of EGPA, recognizing, however, that this has not been compared to the validated dosage of 300 mg monthly.

Central nervous system involvement in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Report of 26 patients and review of the literature.

BACKGROUND: Although peripheral nervous system involvement is common in eosinophilic granulomatosis with polyangiitis (EGPA), central nervous system (CNS) manifestations are poorly described. This study aimed to describe CNS involvement in EGPA. PATIENTS AND METHODS: This retrospective, observational, multicenter study included patients with EGPA and CNS involvement affecting cranial nerves, brain and/or spinal cord. We also undertook a systematic literature review. RESULTS: We analyzed 26 personal cases and 62 previously reported cases. At EGPA diagnosis, asthma was noted in 97%, eosinophilia in 98%, peripheral neuropathy in 55% and cardiac involvement in 41%. 38/71 (54%) were ANCA-positive, with a perinuclear-labeling pattern and/or anti-MPO specificity. CNS was involved in 86% at EGPA diagnosis, preceded EGPA in 2%, and occurred during follow-up in 12% after a median of 24months. Main neurological manifestations were ischemic cerebrovascular lesions in 46 (52%), intracerebral hemorrhage and/or subarachnoid hemorrhage in 21 (24%), loss of visual acuity in 28 (33%) (15 with optic neuritis, 9 with central retinal artery occlusion, 4 with cortical blindness), and cranial nerves palsies in 18 (21%), with 25 patients having ≥1 of these clinical CNS manifestations. Among the 81 patients with assessable neurological responses, 43% had complete responses without sequelae, 43% had partial responses with long-term sequelae and 14% refractory disease. After a mean follow-up of 36months, 11 patients died including 5 from intracerebral hemorrhages. CONCLUSION: EGPA-related CNS manifestations form 4 distinct neurological pictures: ischemic lesions, intracerebral hemorrhages, cranial nerve palsies and loss of visual acuity. Such manifestation should prompt practitioners to consider EGPA in such conditions. Long-term neurological sequelae were common, and intracerebral hemorrhages had the worst prognostic impact.

Anti-IgE Monoclonal Antibody (Omalizumab) in Refractory and Relapsing Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss): Data on Seventeen Patients.

OBJECTIVE: To describe the efficacy and safety of omalizumab, an anti-IgE monoclonal antibody, in patients with refractory and/or relapsing eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA). METHODS: We conducted a nationwide retrospective study including EGPA patients who received omalizumab. Response was defined as the absence of asthma and/or sinonasal exacerbations with a prednisone dosage of ≤7.5 mg/day (complete response) or >7.5 mg/day (partial response). RESULTS: Seventeen patients (median age 45 years) received omalizumab for severe steroid-dependent asthma (88%) and/or sinonasal involvement (18%). After a median follow-up of 22 months, 6 patients (35%) achieved a complete response, 5 patients (30%) achieved a partial response, and 6 patients (35%) had no improvement. The median Birmingham Vasculitis Activity Score decreased from 2.5 at baseline to 0.5 at 12 months. The median number of exacerbations per month decreased from 1 at baseline to 0 at 12 months, and the median forced expiratory volume in 1 second increased from 63% of the percent predicted at baseline to 85% of the percent predicted at 12 months. The median prednisone dosage decreased from 16 mg/day at baseline to 11 mg/day at 6 months and 9 mg/day at 12 months. Omalizumab was discontinued in 8 patients (47%) during follow-up, because of remission (12.5%), adverse event despite disease remission (12.5%), refractory disease (25%), or relapse (50%). Relapses included retrobulbar optic neuritis attributable to EGPA in 2 patients and severe asthma flare in 2 others. CONCLUSION: The results of this study suggest that omalizumab may have a corticosteroid-sparing effect in EGPA patients with asthmatic and/or sinonasal manifestations, but reducing the corticosteroid dose may also increase the risk of severe EGPA flares, which raises the question of the safety of omalizumab in patients with EGPA.

Pituitary involvement in granulomatosis with polyangiitis: report of 9 patients and review of the literature.

Pituitary dysfunction is a rare manifestation of granulomatosis with polyangiitis (GPA) (Wegener). The main aim of this multicenter retrospective study was to describe the characteristics and outcomes of pituitary manifestations in patients with GPA included in the French Vasculitis Study Group database.Among the 819 GPA patients included in the database, 9 (1.1%) had pituitary involvement. The median age at diagnosis of GPA and pituitary involvement was 46 and 50.8 years, respectively. Pituitary involvement was present at onset of GPA in 1 case and occurred later in 8 patients after a median follow up of 58.5 months. When pituitary dysfunction occurred, 8 patients had active disease at other sites including ENT (n = 6), eye (n = 4), or central nervous system (n = 3) involvement. The most common hormonal dysfunctions were diabetes insipidus (n = 7) and hypogonadism (n = 7). Magnetic resonance imaging was abnormal in 7 patients. The most common lesions were an enlargement of the pituitary gland, thickening of the pituitary stalk, and loss of posterior hypersignal on T1-weighed images. All patients were treated with corticosteroid therapy and 8 patients received immunosuppressive agents for the pituitary involvement, including cyclophosphamide (n = 3), rituximab (n = 2), and methotrexate (n = 3). After a median follow-up of 9.2 years, GPA was in complete remission in 7 patients, but 8 patients were still under hormone replacement therapy. Among the 5 patients who had a subsequent MRI, 2 had complete resolution of pituitary lesions.By combining our study and the literature review, the frequency of hypogonadism and diabetes insipidus, among the patients with pituitary dysfunction, can be estimated at 78% and 71% respectively. Despite a high rate of systemic disease remission on maintenance therapy, 86% of the patients had persistent pituitary dysfunction. The patients who recovered from pituitary dysfunction had all been treated by cyclophosphamide.Pituitary disease in GPA occurs mostly several months or years after diagnosis. There is no correlation between hormonal, radiologic, and systemic outcome. Although immunosuppressive drugs improve the systemic disease, hormonal deficiencies usually persist. It is therefore important to shorten diagnostic delays and treat these patients early in the course of disease before irreversible damage occur.

Low serum procalcitonin level accurately predicts the absence of bacteremia in adult patients with acute fever.

The ability of measurement of serum procalcitonin (PCT) levels to differentiate bacteremic from nonbacteremic infectious episodes in patients hospitalized for community-acquired infections was assessed. Serum samples were obtained from adult inpatients with fever to determine the serum PCT level, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). Of 165 patients, 22 (13%) had bacteremic episodes and 143 (87%) had nonbacteremic episodes. PCT levels, CRP levels, and ESRs were significantly higher in bacteremic patients than in nonbacteremic patients (P<.001,.007, and.024, respectively). The best cutoff value for PCT was 0.4 ng/mL, which was associated with a negative predictive value of 98.8%. Area under the receiver operating characteristic curve was 0.83 for PCT, which was significantly higher than that for CRP (0.68; P<.0001) and ESR (0.65; P<.05). A serum PCT level of <0.4 ng/mL accurately rules out the diagnosis of bacteremia. The use of PCT assessment could help physicians limit the number of blood cultures to be processed and the number of antibiotic prescriptions.

A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis.

BACKGROUND: More than 80 transthyretin (TTR) mutations have been described, most associated with amyloidosis. Peripheral neuropathy is the most common clinical presentation in TTR amyloidosis although the carpal tunnel syndrome (CTS) may be the first symptom and skin can be involved, as transthyretin amyloidosis is a systemic disease. CASE REPORT: The 78 year-old proband, belonging to a French family of Italian origin, presented with a 5 year history of peripheral neuropathy in the lower extremities. However, 15 years earlier he had had surgery for bilateral CTS. Amyloidosis was diagnosed on salivary gland and skin biopsies. Immunohistochemistry on skin biopsy was positive using anti-TTR. The proband has 10 siblings, 5 have CTS. METHODS: SSCP and direct sequencing of exons 2, 3, and 4 of the TTR gene were done on DNA from the proband and his brother who had had CTS. To confirm the mutation a PCR-IMRA was done. RESULTS: SSCP analysis of TTR exons 2, 3, and 4 did not suggest a mutation. Sequence analysis of TTR exon 3 revealed heterozygosity in both subjects for a single basepair transversion from A to T in codon 78 (TAC-->TTC) indicating a tyrosine to phenylalanine change. The mutation was confirmed by PCR-IMRA. CONCLUSION: This TTR mutation (Tyr78Phe) is associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis. It is also associated with late onset of the disease.